Defects in oxidative phosphorylation (OXPHOS) have been associated with various neurodegenerative processes. In this application we propose to produce and analyze novel mouse models of OXPHOS deficiency in the CNS, specifically in the cortex/hippocampus/striatum or in the substantia nigra (aim#l). These models, affecting complexes I, II, III and IV, will complement the ones previously obtained and after characterization will be used to better understand the role of specific OXPHOS defects in neurodegeneration (aim#2). Finally, we 'will also take advantage of these models and to develop novel therapeutic approaches to OXPHOS defects in the CNS (aim#3)[unreadable] This approach will allow us to define the susceptibilities of different neuronal populations to the various OXPHOS defects, shedding light on the pathogenesis of both bona fide mitochondrial disorders and age-related neurodegenerative diseases. The general hypotheses and questions this proposal will test are: i) Are different neuronal populations more susceptible to defects in specific OXPHOS complexes? iii) Do defects in specific respiratory chain complexes lead to different neurodegenerative phenotypes? iv) Are neurodegenerative phenotypes associated with defects in specific complex caused by different levels of oxidative damage or protein aggregation? v) Can we improve these neurodegenerative phenotypes by manipulating the mitochondrial biogenesis?